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Meloni A, Saba L, Positano V, Taccori M, Pistoia L, De Marco E, Sanna PMG, Longo F, Giovangrossi P, Gerardi C, Barone A, Visceglie D, Barra V, Clemente A, Cau R. Left ventricular diastolic and systolic functions by cardiac magnetic resonance in beta-thalassemia major: correlation with clinical findings and cardiac complications. THE INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING 2025; 41:847-857. [PMID: 39928284 DOI: 10.1007/s10554-025-03352-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 01/30/2025] [Indexed: 02/11/2025]
Abstract
This cross-sectional study explored the association of left ventricular (LV) fractional area change (FAC) with demographic characteristics, clinical data, cardiovascular magnetic resonance (CMR) findings, and cardiac complications (heart failure and arrythmias) in patients with beta-thalassemia major (β-TM). We included 292 β-TM patients (151 females, 36.72 ± 11.76 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia project and 20 healthy controls (8 females, 36.97 ± 3.54 years). CMR was used to assess FAC and derive LV systolic and diastolic indexes, to quantify myocardial iron overload (MIO) by the T2* technique and LV volumes and ejection fraction, and to detect late gadolinium enhancement (LGE). Healthy subjects and β-TM patients showed comparable LV systolic and diastolic indexes. In β-TM, the LV systolic index was significantly correlated with global heart T2* values, and patients with significant MIO (T2*<20ms) were more likely to have a reduced LV systolic index compared to those without MIO (odds ratio-OR = 3.13; p = 0.013). In multivariate analysis, global heart T2* values and positive LGE emerged as independent determinants of the LV systolic index. The number of segments with LGE inversely correlated with the LV systolic index (p = 0.003). Patients with a reduced LV systolic index were more likely to have cardiac diseases than those with a normal LV systolic index (OR = 5.34; p < 0.0001). No significant correlates were found for the LV diastolic index. In well-treated β-TM patients, MIO and LGE were the strongest determinants of the LV systolic index, and a reduced LV systolic index was associated with an increased risk of cardiac complications.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1, Pisa, 56124, Italy.
| | - Luca Saba
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari - Polo di Monserrato, Cagliari, Italy
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1, Pisa, 56124, Italy
| | - Mauro Taccori
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari - Polo di Monserrato, Cagliari, Italy
| | - Laura Pistoia
- U.O.C. Ricerca Clinica, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Emanuela De Marco
- U.O. Oncoematologia Pediatrica, Azienda Ospedaliero Universitaria Pisana- Stabilimento S. Chiara, Pisa, Italy
| | | | - Filomena Longo
- Unità Operativa Day Hospital Della Talassemia e Delle Emoglobinopatie, Azienda Ospedaliero-Universitaria "S. Anna", Cona- Ferrara, Italy
| | - Piera Giovangrossi
- Servizio di Immunoematologia e Medicina Trasfusionale, Ospedale S. M. Goretti, Latina, Italy
| | - Calogera Gerardi
- Unità Operativa Semplice Dipartimentale di Talassemia, Presidio Ospedaliero "Giovanni Paolo II" - Distretto AG2 di Sciacca, Sciacca, AG, Italy
| | - Angelica Barone
- Unità Operativa di Pediatria e Oncoematologia Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Domenico Visceglie
- Servizio di Immunoematologia e Medicina Trasfusionale, Ospedale "Di Venere", Bari, Italy
| | - Valerio Barra
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Alberto Clemente
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Riccardo Cau
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari - Polo di Monserrato, Cagliari, Italy
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Meloni A, Positano V, Ricchi P, Pepe A, Cau R. What is the importance of monitoring iron levels in different organs over time with magnetic resonance imaging in transfusion-dependent thalassemia patients? Expert Rev Hematol 2025; 18:291-299. [PMID: 40152085 DOI: 10.1080/17474086.2025.2486379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/19/2025] [Accepted: 03/26/2025] [Indexed: 03/29/2025]
Abstract
INTRODUCTION Iron overload is the main pathophysiological driver of organ damage in transfusion-dependent thalassemia (TDT). Magnetic resonance imaging (MRI) provides detailed insights into the distribution and severity of iron accumulation in the different organs. AREAS COVERED This special report describes the impact of MRI on clinical and therapeutic management and short- and long-term outcomes in TDT patients. PubMed, Scopus, and Google Scholar databases were searched to identify the relevant studies published before November 2024. EXPERT OPINION Cardiac and hepatic MRI are now well-established modalities, integrated into the clinical practice. They have become essential for tailoring iron chelation therapies to the specific patient's needs and for monitoring treatment efficacy. The improved control of cardiac iron burden has translated into reduced morbidity and mortality. The MRI accessibility remains limited in resource-limited settings and progress in this field relies on educating and training centers to ensure accurate execution and interpretation. The clinicopathological significance, prognostic value, and reproducibility of pancreatic iron levels assessment have been established, charting a path toward its clinical use. There are limited data about renal, adrenal, and pituitary iron deposition, and more research is needed to fully establish the functional significance and to standardize and validate the MRI protocols.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Paolo Ricchi
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Alessia Pepe
- Institute of Radiology, Department of Medicine, University of Padua, Padua, Italy
| | - Riccardo Cau
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari - Polo di Monserrato, Monserrato, Italy
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Meloni A, Pistoia L, Spasiano A, Sorrentino F, Messina G, Santodirocco M, Borsellino Z, Cecinati V, Positano V, Restaino G, Schicchi N, Grassedonio E, Vallone A, Emdin M, Clemente A, Barison A. Prevalence and Correlates of Dilated and Non-Dilated Left Ventricular Cardiomyopathy in Transfusion-Dependent Thalassemia: Data from a National, Multicenter, Observational Registry. J Cardiovasc Dev Dis 2025; 12:103. [PMID: 40137101 PMCID: PMC11943376 DOI: 10.3390/jcdd12030103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/10/2025] [Accepted: 03/14/2025] [Indexed: 03/27/2025] Open
Abstract
We investigated the prevalence, clinical characteristics, and prognostic role of dilated cardiomyopathy (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC) in patients with transfusion-dependent β-thalassemia (β-TDT). We retrospectively included 415 β-TDT patients who underwent cardiovascular magnetic resonance to quantify myocardial iron overload (MIO) and biventricular function parameters and to detect replacement myocardial fibrosis. Demographic and laboratory parameters were comparable among patients with no overt cardiomyopathy (NOCM; n = 294), DCM (n = 12), and NDLVC (n = 109), while cardiac size and systolic function were significantly different. Compared to NOCM patients, DCM and NDLVC patients had a higher prevalence of MIO and replacement myocardial fibrosis. During a mean follow-up of 57.03 ± 18.01 months, cardiac complications occurred in 32 (7.7%) patients: 15 heart failures, 15 supraventricular arrhythmias, and 2 pulmonary hypertensions. Compared to the NOCM group, both the NDLVC and the DCM groups were associated with a significantly increased risk of cardiac complications (hazard ratio = 4.26 and 8.81, respectively). In the multivariate analysis, the independent predictive factors were age, MIO, and the presence of DCM and NDLVC versus the NOCM phenotype. In β-TDT, the detection of NDLVC and DCM phenotypes may hold value in predicting cardiac outcomes.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.)
| | - Laura Pistoia
- Unità Operativa Semplice Dipartimentale Ricerca Clinica, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy;
| | - Anna Spasiano
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “A. Cardarelli”, 80131 Napoli, Italy;
| | - Francesco Sorrentino
- Unità Operativa Semplice Dipartimentale Day Hospital Talassemici, Ospedale “Sant’Eugenio”, 00143 Roma, Italy;
| | - Giuseppe Messina
- Centro Microcitemie, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, 89100 Reggio Calabria, Italy;
| | - Michele Santodirocco
- Centro Microcitemia—Day Hospital Thalassemia Poliambulatorio “Giovanni Paolo II”, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Zelia Borsellino
- Unità Operativa Complessa Ematologia con Talassemia, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico “Benfratelli-Di Cristina”, 90134 Palermo, Italy;
| | - Valerio Cecinati
- Struttura Semplice di Microcitemia, Ospedale “SS. Annunziata”, 74123 Taranto, Italy;
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.)
| | - Gennaro Restaino
- Radiology Department, Responsible Research Hospital, 86100 Campobasso, Italy;
| | - Nicolò Schicchi
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I-Lancisi-Salesi”, 60020 Ancona, Italy;
| | - Emanuele Grassedonio
- Sezione di Scienze Radiologiche—Dipartimento di Biopatologia e Biotecnologie Mediche, Policlinico “Paolo Giaccone”, 90127 Palermo, Italy;
| | - Antonino Vallone
- Reparto di Radiologia, Azienda Ospedaliera “Garibaldi” Presidio Ospedaliero Nesima, 95126 Catania, Italy;
| | - Michele Emdin
- Cardiology and Cardiovascular Medicine, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy;
- Institute of Life Sciences, Scuola Superiore Sant’Anna, 56124 Pisa, Italy
| | - Alberto Clemente
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy;
| | - Andrea Barison
- Cardiology and Cardiovascular Medicine, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy;
- Institute of Life Sciences, Scuola Superiore Sant’Anna, 56124 Pisa, Italy
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Selim OMHZ, Ibrahim ASAH, Aly NH, Hegazy SNA, Ebeid FSE. Early detection of myocardial iron overload in patients with β-thalassemia major using cardiac magnetic resonance T1 mapping. Magn Reson Imaging 2024; 114:110250. [PMID: 39368520 DOI: 10.1016/j.mri.2024.110250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/14/2024] [Accepted: 09/29/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND The T2* technique, used for quantifying myocardial iron content (MIC), has limitations in detecting early myocardial iron overload (MIO). The in vivo mapping of the myocardial T1 relaxation time is a promising alternative for the early detection and management of MIO. METHODS 32 β-thalassemia major (βTM) patients aged 11.5 ± 4 years and 32 healthy controls were recruited and underwent thorough clinical and laboratory assessments. The mid-level septal iron overload was measured through T1 mapping using a modified Look-Locker inversion recovery sequence with a 3 (3 s) 3 (3 s) 5 scheme. Septum was divided at the mentioned level into 3 zones corresponding to segments 8 and 9 in the cardiac segmentation model. RESULTS 21.9 % of βTM had clinical cardiac morbidity. The cut-off of T1 mapping of hepatic and myocardium to differentiate between the patients and control groups was ≤466 and ≥ 923 ms respectively. The T1 technique was able to detect 4 patients with high MIC, two of them were not detected by the T2* technique. There was a statistically significant correlation between the average T1 values of the studied zones in patients with βTM and the liver iron content (LIC), the T1 values within segment 8 of the liver, age of patients, the age at first transfusion, age of splenectomy and serum ferritin value. CONCLUSION The addition of the T1 mapping sequence to the conventional T2* technique was able to increase the efficacy of the MIC detection protocol by earlier detection of MIO. This would guide chelation therapy to decrease myocardial morbidity.
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Affiliation(s)
- Omar Mourad Hassan Zaki Selim
- Diagnostic and Interventional Radiology and Molecular Imaging Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed Samir Abdel Hakim Ibrahim
- Diagnostic and Interventional Radiology and Molecular Imaging Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nihal Hussien Aly
- Pediatric Hematology Oncology and BMT Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sherif Nabil Abbas Hegazy
- Diagnostic and Interventional Radiology and Molecular Imaging Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Fatma Soliman Elsayed Ebeid
- Pediatric Hematology Oncology and BMT Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Faculty of Medicine Ain Shams University Research Institute-Clinical Research Center (MASRI-CRC), Faculty of Medicine, Ain Shams University, Cairo, Egypt.
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Meloni A, Saba L, Cademartiri F, Positano V, Pistoia L, Cau R. Cardiovascular magnetic resonance in β-thalassemia major: beyond T2. LA RADIOLOGIA MEDICA 2024; 129:1812-1822. [PMID: 39511065 DOI: 10.1007/s11547-024-01916-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/29/2024] [Indexed: 11/15/2024]
Abstract
Β-thalassemia major (TM) patients underwent regular transfusions to prevent complications of chronic anemia. However, these regular transfusions result in progressive iron accumulation in vital organs, including the heart. Myocardial iron overload can lead to cardiac dysfunction and ultimately to heart failure. Diagnosis of cardiac dysfunction in β-TM patients is usually made through clinical examination, electrocardiogram, and echocardiography. Cardiac magnetic resonance (CMR), through the measurement of T2* relaxation time, represents the diagnostic modality of choice for assessing myocardial iron overload and guiding the iron chelation therapy. Despite a tailored chelation therapy reducing myocardial iron overload, heart failure remains the leading cause of morbidity and mortality even in well-treated β-TM patients. Advances in CMR, including myocardial strain, parametric mapping (T1, T2, and extracellular volume), and late gadolinium enhancement (LGE) measurements, have expanded its role in the diagnosis, prognosis, and follow-up of these patients. This review seeks to offer a thorough overview of the potential uses of CMR in β-TM, extending beyond the established role of T2* measurement in guiding chelation therapy. It delves into the emerging applications of new CMR imaging biomarkers that could improve the overall management of β-TM patients.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Luca Saba
- Dipartimento Di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari-Polo di Monserrato, S.S.554 Monserrato, 09045, Cagliari, Italy
| | - Filippo Cademartiri
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Laura Pistoia
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- U.O.C. Ricerca Clinica, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Riccardo Cau
- Dipartimento Di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari-Polo di Monserrato, S.S.554 Monserrato, 09045, Cagliari, Italy.
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Salimi Z, Afsharinasab M, Rostami M, Eshaghi Milasi Y, Mousavi Ezmareh SF, Sakhaei F, Mohammad-Sadeghipour M, Rasooli Manesh SM, Asemi Z. Iron chelators: as therapeutic agents in diseases. Ann Med Surg (Lond) 2024; 86:2759-2776. [PMID: 38694398 PMCID: PMC11060230 DOI: 10.1097/ms9.0000000000001717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/03/2024] [Indexed: 05/04/2024] Open
Abstract
The concentration of iron is tightly regulated, making it an essential element. Various cellular processes in the body rely on iron, such as oxygen sensing, oxygen transport, electron transfer, and DNA synthesis. Iron excess can be toxic because it participates in redox reactions that catalyze the production of reactive oxygen species and elevate oxidative stress. Iron chelators are chemically diverse; they can coordinate six ligands in an octagonal sequence. Because of the ability of chelators to trap essential metals, including iron, they may be involved in diseases caused by oxidative stress, such as infectious diseases, cardiovascular diseases, neurodegenerative diseases, and cancer. Iron-chelating agents, by tightly binding to iron, prohibit it from functioning as a catalyst in redox reactions and transfer iron and excrete it from the body. Thus, the use of iron chelators as therapeutic agents has received increasing attention. This review investigates the function of various iron chelators in treating iron overload in different clinical conditions.
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Affiliation(s)
- Zohreh Salimi
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
| | - Mehdi Afsharinasab
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran
| | - Mehdi Rostami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
| | - Seyedeh Fatemeh Mousavi Ezmareh
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
| | - Fariba Sakhaei
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
| | - Maryam Mohammad-Sadeghipour
- Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman
| | | | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
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Cortés P, Elsayed AA, Stancampiano FF, Barusco FM, Shapiro BP, Bi Y, Heckman MG, Peng Z, Kempaiah P, Palmer WC. Clinical and genetic predictors of cardiac dysfunction assessed by echocardiography in patients with hereditary hemochromatosis. THE INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING 2024; 40:45-53. [PMID: 37821712 DOI: 10.1007/s10554-023-02973-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 09/24/2023] [Indexed: 10/13/2023]
Abstract
PURPOSE Hereditary hemochromatosis (HH) may cause iron deposition in cardiac tissue. We aimed to describe the echocardiographic findings in patients with HH and identify risk factors for cardiac dysfunction. METHODS In this retrospective study, we included patients with HH who underwent transthoracic echocardiography at our tertiary care center between August 2000 and July 2022. We defined three primary outcomes for cardiac dysfunction: 1) left ventricular ejection fraction (LVEF) < 55%, 2) ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') > 15, and 3) global longitudinal strain (GLS) < 18. Multivariable logistic regression was utilized to identify predictors of cardiac dysfunction. RESULTS 582 patients (median age 57 years, 61.2% male) were included. The frequency of LVEF < 55%, E/e' > 15 and GLS < 18 was 9.0% (52/580), 9.6% (51/534) and 20.2% (25/124), respectively. In multivariable analysis, non-White race, age, and hypertension were associated with E/e' > 15. No specific HFE genetic mutation was associated with LVEF < 55%. A history of myocardial infarction was strongly associated with both LVEF < 55% and E/e' > 15. In patients with LVEF ≥ 55%, the C282Y/H63D genetic mutation was associated with reduced likelihood of E/e' > 15, p = 0.024. Patients with C282Y/H63D had a higher frequency of myocardial infarction. Smoking and alcohol use were significantly associated with GLS < 18 in unadjusted analysis. CONCLUSION We found the traditional risk factors of male sex, and history of myocardial infarction or heart failure, were associated with a reduced LVEF, irrespective of the underlying HFE genetic mutation. Patients with a C282Y/H63D genetic mutation had a higher frequency of myocardial infarction, yet this mutation was associated with reduced odds of diastolic dysfunction compared to other genetic mutations in patients with a normal LVEF.
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Affiliation(s)
- Pedro Cortés
- Division of Community Internal Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA
| | | | | | | | - Brian P Shapiro
- Division of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Yan Bi
- Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Michael G Heckman
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Zhongwei Peng
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Prakash Kempaiah
- Division of Infectious Diseases, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - William C Palmer
- Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
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Abstract
Thalassemias are among the most common hereditary diseases in the world because heterozygosity offers protection against malarial infection. Affected individuals have variable expression of alpha or beta chains that lead to their unbalanced utilization during hemoglobin formation, oxidative stress, and apoptosis of red cell precursors prior to maturation. Some individuals produce sufficient hemoglobin to survive but suffer the vascular stress imposed by chronic anemia and ineffective erythropoiesis. In other patients, mature red cell formation is insufficient, and chronic transfusions are required-suppressing anemia and ineffective erythropoiesis but at the expense of iron overload. The cardiovascular consequences of thalassemia have changed dramatically over the previous five decades because of evolving treatment practices. This review summarizes this evolution, focusing on complications and management pertinent to modern patient cohorts.
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Affiliation(s)
- John C Wood
- Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, California, USA
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Kontoghiorghes GJ. Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs. Int J Mol Sci 2023; 24:16749. [PMID: 38069073 PMCID: PMC10706143 DOI: 10.3390/ijms242316749] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/19/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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10
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Meloni A, Pistoia L, Ricchi P, Positano V, Longo F, Borsellino Z, Cecinati V, Messina G, Corigliano E, Rosso R, Righi R, Peritore G, Renne S, Vallone A, Cademartiri F. Pancreatic T2* Magnetic Resonance Imaging for Prediction of Cardiac Arrhythmias in Transfusion-Dependent Thalassemia. J Clin Med 2023; 12:6015. [PMID: 37762955 PMCID: PMC10531669 DOI: 10.3390/jcm12186015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/08/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
We assessed the value of pancreatic T2* magnetic resonance imaging (MRI) for predicting cardiac events from a large prospective database of transfusion-dependent thalassemia (TDT) patients. We considered 813 TDT patients (36.47 ± 10.71 years, 54.6% females) enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. MRI was used to measure hepatic, pancreatic, and cardiac iron overload (IO), to assess biventricular function and atrial dimensions, and to detect replacement myocardial fibrosis. The mean follow-up was 50.51 ± 19.75 months. Cardiac complications were recorded in 21 (2.6%) patients: one with heart failure (HF) and 20 with arrhythmias. The single patient who developed HF had, at the baseline MRI, a reduced pancreas T2*. Out of the 20 recorded arrhythmias, 17 were supraventricular. Pancreatic T2* values were a significant predictor of future arrhythmia-related events (hazard ratio = 0.89; p = 0.015). Pancreas T2* remained significantly associated with future arrhythmias after adjusting for any other univariate predictor (age and male sex, diabetes, history of previous arrhythmias, or left atrial area index). According to the receiver-operating characteristic curve analysis for arrhythmias, a pancreas T2* < 6.73 ms was the optimal cut-off value. In TDT, pancreatic iron levels had significant prognostic power for arrhythmias. Regular monitoring and the development of targeted interventions to manage pancreatic IO may help improve patient outcomes.
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Affiliation(s)
- Antonella Meloni
- Department of Radiology, Fondazione Gabriele Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (L.P.); (V.P.)
- Unità Operativa Complessa Bioingegneria, Fondazione Gabriele Monasterio CNR-Regione Toscana, 56124 Pisa, Italy
| | - Laura Pistoia
- Department of Radiology, Fondazione Gabriele Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (L.P.); (V.P.)
- Unità Operativa Semplice a Valenza Dipartimentale Ricerca Clinica, Fondazione Gabriele Monasterio CNR-Regione Toscana, 56124 Pisa, Italy
| | - Paolo Ricchi
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “Antonio Cardarelli”, 80131 Napoli, Italy;
| | - Vincenzo Positano
- Department of Radiology, Fondazione Gabriele Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (L.P.); (V.P.)
- Unità Operativa Complessa Bioingegneria, Fondazione Gabriele Monasterio CNR-Regione Toscana, 56124 Pisa, Italy
| | - Filomena Longo
- Unità Operativa Day Hospital della Talassemia e delle Emoglobinopatie, Azienda Ospedaliero-Universitaria “S. Anna”, 44124 Cona, Italy;
| | - Zelia Borsellino
- Unità Operativa Complessa Ematologia con Talassemia, ARNAS Civico “Benfratelli-Di Cristina”, 90134 Palermo, Italy;
| | - Valerio Cecinati
- Struttura Semplice di Microcitemia, Ospedale “Santissima Annunziata”, 74123 Taranto, Italy;
| | - Giuseppe Messina
- Centro Microcitemie, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, 89100 Reggio Calabria, Italy;
| | - Elisabetta Corigliano
- Ematologia Microcitemia, Ospedale San Giovanni di Dio—ASP Crotone, 88900 Crotone, Italy;
| | - Rosamaria Rosso
- Unità Operativa Talassemie ed Emoglobinopatie, Azienda Ospedaliero-Universitaria Policlinico “Vittorio Emanuele”, 95100 Catania, Italy;
| | - Riccardo Righi
- Diagnostica per Immagini e Radiologia Interventistica, Ospedale del Delta, 44023 Lagosanto, Italy;
| | - Giuseppe Peritore
- Unità Operativa Complessa di Radiologia, ARNAS Civico “Benfratelli-Di Cristina”, 90127 Palermo, Italy;
| | - Stefania Renne
- Struttura Complessa di Cardioradiologia-UTIC, Presidio Ospedaliero “Giovanni Paolo II”, 88046 Lamezia Terme, Italy;
| | - Antonino Vallone
- Reparto di Radiologia, Azienda Ospedaliera “Garibaldi” Presidio Ospedaliero Nesima, 95126 Catania, Italy;
| | - Filippo Cademartiri
- Department of Radiology, Fondazione Gabriele Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (L.P.); (V.P.)
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11
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Kontoghiorghes GJ. The Vital Role Played by Deferiprone in the Transition of Thalassaemia from a Fatal to a Chronic Disease and Challenges in Its Repurposing for Use in Non-Iron-Loaded Diseases. Pharmaceuticals (Basel) 2023; 16:1016. [PMID: 37513928 PMCID: PMC10384919 DOI: 10.3390/ph16071016] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/13/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood-brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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12
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Kontoghiorghes GJ. Deferiprone and Iron-Maltol: Forty Years since Their Discovery and Insights into Their Drug Design, Development, Clinical Use and Future Prospects. Int J Mol Sci 2023; 24:ijms24054970. [PMID: 36902402 PMCID: PMC10002863 DOI: 10.3390/ijms24054970] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol-iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol-iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world's population. Detailed insights into different aspects of drug development associated with L1 and the maltol-iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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13
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Shah R, Shah A, Badawy SM. An evaluation of deferiprone as twice-a-day tablets or in combination therapy for the treatment of transfusional iron overload in thalassemia syndromes. Expert Rev Hematol 2023; 16:81-94. [PMID: 36755516 PMCID: PMC9992344 DOI: 10.1080/17474086.2023.2178409] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 02/06/2023] [Indexed: 02/10/2023]
Abstract
INTRODUCTION Regular blood transfusions in patients with thalassemia syndromes can cause iron overload resulting in complications including cirrhosis, heart problems, or endocrine abnormalities. To prevent iron overload toxicity in these patients, three iron chelators are currently FDA-approved for use: deferoxamine, deferasirox, and deferiprone. In the United States, deferiprone has been approved for three times daily dosing since 2011 and has recently gained approval for twice-daily administration. AREAS COVERED A PubMed literature search was performed with the keywords 'deferiprone' and 'thalassemia.' Relevant original research studying deferiprone's effects on transfusional iron overload in patients with thalassemia syndromes was included. Exclusion criteria included case reports and review papers. Deferiprone is effective at reducing serum ferritin levels in patients with iron overload. Twice-daily administration provides a similar level of iron chelation as three times daily dosing with a comparable side effect profile and increased patient acceptability. EXPERT OPINION New studies are highlighting deferiprone's potential for combination therapy with either deferoxamine or deferasirox to improve iron chelation. Deferiprone's ability to significantly decrease cardiac and liver iron content can be utilized in other transfusion-dependent hematologic conditions, as evidenced by its recent approval for use in the United States for sickle cell disease or other anemias.
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Affiliation(s)
- Richa Shah
- Division of Hematology, Oncology, and Stem Cell Transplant, Lurie Children’s Hospital of Chicago, Chicago, IL, 60611, USA
| | - Aashaka Shah
- University of Illinois College of Medicine, Chicago, IL, 60612, USA
| | - Sherif M. Badawy
- Division of Hematology, Oncology, and Stem Cell Transplant, Lurie Children’s Hospital of Chicago, Chicago, IL, 60611, USA
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
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14
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Raj V, Gowda S, Kothari R. Myocardial tissue characterization by cardiac magnetic resonance: A primer for the clinician. JOURNAL OF THE INDIAN ACADEMY OF ECHOCARDIOGRAPHY & CARDIOVASCULAR IMAGING 2023. [DOI: 10.4103/jiae.jiae_44_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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15
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Kontoghiorghes GJ. Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology. Int J Mol Sci 2022; 23:ijms23126735. [PMID: 35743183 PMCID: PMC9223898 DOI: 10.3390/ijms23126735] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 02/01/2023] Open
Abstract
The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a “magic bullet” drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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16
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Studying the some biochemical parameters for thalassemia patients in AL-Najaf province. Int J Health Sci (Qassim) 2022. [DOI: 10.53730/ijhs.v6ns4.6313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The current study aims to study some biochemical indicators for thalassemia patients in the Najaf governorate, and the study included 25 patients with major beta thalassemia during the period from November 2019 to February 2020 and their ages ranged between (2 - 65) years and 15 healthy people who arenot He had genetic blood diseases and their ages ranged between (2-65) years. The results of the study showed that there are in some biochemical indicators, as there was a significant increase in the level of the enzyme of liver function ALT that was the focus in patients 23.74 ± 29.53 U\L and in healthy people it was 4.61 ± 11.67U\L Also, the creatinine concentration patients 9.92 ± 26.08 mmol\L and in healthy was, 68.06 ± 51.54 mmol\L, Except for urea, we notice that there was a decrease in its concentration in patients 0.89 ± 3.96 mmol\L and in healthy was 1.03 ± 2.36 mmol\L, There was an increase in the concentration of iron in the blood in patients 382.05 ±64.37 Umol\L And in healthy was 9.48 ± 61.36 Umol\L, as well as a decrease in the concentration of glucose in patients and an increase in healthy people
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17
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Safety and Efficacy of the New Combination Iron Chelation Regimens in Patients with Transfusion-Dependent Thalassemia and Severe Iron Overload. J Clin Med 2022; 11:jcm11072010. [PMID: 35407617 PMCID: PMC8999930 DOI: 10.3390/jcm11072010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 11/24/2022] Open
Abstract
The aim of this study is the evaluation of the safety and the efficacy of long-term combination therapy deferasirox plus desferrioxamine and deferasirox plus deferiprone in a large group of transfusion-dependent thalassemia patients with high values of serum ferritin and/or magnetic resonance, indicative of severe liver and cardiac iron accumulation. Sixteen adults with transfusion-dependent thalassemia were treated simultaneously with deferasirox plus desferrioxamine, while another 42 patients (seven children) were treated with deferasirox plus deferiprone. The hepatic and cardiac iron overload was assessed prior to treatment and then annually with magnetic resonance imaging, and the serum ferritin was measured monthly. Adverse events were checked at each transfusion visit. The safety of both the combinations was consistent with established monotherapies. Both treatments were able to decrease the serum ferritin and liver iron concentration over time, depending on the level of compliance with therapy. Cardiac iron measured as R2* did not significantly change in patients treated with deferasirox plus desferrioxamine. Most patients with MRI indicative of myocardial siderosis at the beginning of treatment reached normal values of cardiac iron at the last determination if treated with deferasirox plus desferrioxamine. The greatest limitation of these therapies was low patient adherence to the two drugs, which is not surprising considering that the need for an intensive chelation is generally linked to previous issues of compliance.
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18
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Kumfu S, Chattipakorn SC, Chattipakorn N. Iron overload cardiomyopathy: Using the latest evidence to inform future applications. Exp Biol Med (Maywood) 2022; 247:574-583. [PMID: 35130741 DOI: 10.1177/15353702221076397] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Iron overload can be the result of either dysregulated iron metabolism in the case of hereditary hemochromatosis or repeated blood transfusions in the case of secondary hemochromatosis (e.g. in β-thalassemia and sickle cell anemia patients). Under iron overload conditions, transferrin (Tf) saturation leads to an increase in non-Tf bound iron which can result in the generation of reactive oxygen species (ROS). These excess ROS can damage cellular components, resulting in the dysfunction of vital organs including iron overload cardiomyopathy (IOC). Multiple studies have demonstrated that L-type and T-type calcium channels are the main routes for iron uptake in the heart, and that calcium channel blockers, given either individually or in combination with standard iron chelators, confer cardioprotective effects under iron overload conditions. Treatment with antioxidants may also provide therapeutic benefits. Interestingly, recent studies have suggested that mitochondrial dynamics and regulated cell death (RCD) pathways are potential targets for pharmacological interventions against iron-induced cardiomyocyte injury. In this review, the potential therapeutic roles of iron chelators, antioxidants, iron uptake/metabolism modulators, mitochondrial dynamics modulators, and inhibitors of RCD pathways in IOC are summarized and discussed.
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Affiliation(s)
- Sirinart Kumfu
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
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19
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Shah FT, Porter JB, Sadasivam N, Kaya B, Moon JC, Velangi M, Ako E, Pancham S. Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias. Br J Haematol 2022; 196:336-350. [PMID: 34617272 DOI: 10.1111/bjh.17839] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/10/2021] [Accepted: 09/02/2021] [Indexed: 01/19/2023]
Affiliation(s)
- Farrukh T Shah
- Department of Haematology, Whittington Health, London, UK
| | - John B Porter
- Department of Haematology, University College Hospitals, London, UK
| | - Nandini Sadasivam
- Department of Haematology, Manchester Royal Infirmary, Manchester, UK
| | - Banu Kaya
- Department of Paediatric Haematology and Oncology, Barts Health NHS Trust, London, UK
| | - James C Moon
- Department of Cardiovascular Imaging, Barts Heart Centre, St Bartholomew's Hospital, London, UK
- Institutes for Cardiovascular Science, University College London, London, UK
| | - Mark Velangi
- Department of Haematology, Birmingham Children's Hospital, Birmingham, UK
| | - Emmanuel Ako
- Department of Cardiology, Chelsea and Westminster Hospital, London, UK
| | - Shivan Pancham
- Department of Haematology, Sandwell and West Birmingham NHS Trust, West Bromwich, UK
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20
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De Simone G, Quattrocchi A, Mancini B, di Masi A, Nervi C, Ascenzi P. Thalassemias: From gene to therapy. Mol Aspects Med 2021; 84:101028. [PMID: 34649720 DOI: 10.1016/j.mam.2021.101028] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/19/2021] [Indexed: 12/26/2022]
Abstract
Thalassemias (α, β, γ, δ, δβ, and εγδβ) are the most common genetic disorders worldwide and constitute a heterogeneous group of hereditary diseases characterized by the deficient synthesis of one or more hemoglobin (Hb) chain(s). This leads to the accumulation of unstable non-thalassemic Hb chains, which precipitate and cause intramedullary destruction of erythroid precursors and premature lysis of red blood cells (RBC) in the peripheral blood. Non-thalassemic Hbs display high oxygen affinity and no cooperativity. Thalassemias result from many different genetic and molecular defects leading to either severe or clinically silent hematologic phenotypes. Thalassemias α and β are particularly diffused in the regions spanning from the Mediterranean basin through the Middle East, Indian subcontinent, Burma, Southeast Asia, Melanesia, and the Pacific Islands, whereas δβ-thalassemia is prevalent in some Mediterranean regions including Italy, Greece, and Turkey. Although in the world thalassemia and malaria areas overlap apparently, the RBC protection against malaria parasites is openly debated. Here, we provide an overview of the historical, geographic, genetic, structural, and molecular pathophysiological aspects of thalassemias. Moreover, attention has been paid to molecular and epigenetic pathways regulating globin gene expression and globin switching. Challenges of conventional standard treatments, including RBC transfusions and iron chelation therapy, splenectomy and hematopoietic stem cell transplantation from normal donors are reported. Finally, the progress made by rapidly evolving fields of gene therapy and gene editing strategies, already in pre-clinical and clinical evaluation, and future challenges as novel curative treatments for thalassemia are discussed.
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Affiliation(s)
- Giovanna De Simone
- Dipartimento di Scienze, Università Roma Tre, Viale Guglielmo Marconi 446, 00146, Roma, Italy
| | - Alberto Quattrocchi
- Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Facoltà di Farmacia e Medicina, "Sapienza" Università di Roma, Corso della Repubblica, 79, 04100, Latina, Italy
| | - Benedetta Mancini
- Dipartimento di Scienze, Università Roma Tre, Viale Guglielmo Marconi 446, 00146, Roma, Italy
| | - Alessandra di Masi
- Dipartimento di Scienze, Università Roma Tre, Viale Guglielmo Marconi 446, 00146, Roma, Italy
| | - Clara Nervi
- Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Facoltà di Farmacia e Medicina, "Sapienza" Università di Roma, Corso della Repubblica, 79, 04100, Latina, Italy.
| | - Paolo Ascenzi
- Dipartimento di Scienze, Università Roma Tre, Viale Guglielmo Marconi 446, 00146, Roma, Italy; Accademia Nazionale dei Lincei, Via della Lungara 10, 00165, Roma, Italy.
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21
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Kontoghiorghes GJ. Differences between the European Union and United States of America in Drug Regulatory Affairs Affect Global Patient Safety Standards and Public Health Awareness: The Case of Deferasirox and Other Iron Chelating Drugs. MEDICINES (BASEL, SWITZERLAND) 2021; 8:36. [PMID: 34357152 PMCID: PMC8304852 DOI: 10.3390/medicines8070036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/17/2021] [Accepted: 07/05/2021] [Indexed: 06/13/2023]
Abstract
Regulatory policies on drugs have a major impact on patient safety and survival. Some pharmaceutical companies employ all possible methods to achieve maximum sales in relation to the monopoly of their patented drugs, leading sometimes to irregularities and illegal activities. Misinformation on the orphan drug deferasirox has reached the stage of criminal investigations and fines exceeding USD 100 million. Additional lawsuits of USD 3.5 billion for damages and civil fines were also filed by the FBI of the USA involving deferasirox and mycophenolic acid, which were later settled with an additional fine of USD 390 million. Furthermore, a USD 345 million fine was also settled for bribes and other illegal overseas operations including an EU country. However, no similar fines for illegal practises or regulatory control violations have been issued in the EU. Misconceptions and a lack of clear guidelines for the use of deferasirox in comparison to deferiprone and deferoxamine appear to reduce the effective treatment prospects and to increase the toxicity risks for thalassaemia and other iron loaded patients. Similar issues have been raised for the activities of other pharmaceutical companies promoting the use of new patented versus generic drugs. Treatments for different categories of patients using new patented drugs are mostly market driven with no clear safeguards or guidelines for risk/benefit assessment indications or for individualised effective and safe optimum therapies. There is a need for the establishment of an international organisation, which can monitor and assess the risk/benefit assessment and marketing of drugs in the EU and globally for the benefit of patients. The pivotal role of the regulatory drug authorities and the prescribing physicians for identifying individualised optimum therapies is essential for improving the survival and safety of millions of patients worldwide.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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22
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Chaosuwannakit N, Makarawate P, Wanitpongpun C. The Importance of Cardiac T2* Magnetic Resonance Imaging for Monitoring Cardiac Siderosis in Thalassemia Major Patients. ACTA ACUST UNITED AC 2021; 7:130-138. [PMID: 33919601 PMCID: PMC8167609 DOI: 10.3390/tomography7020012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/13/2021] [Accepted: 04/15/2021] [Indexed: 01/19/2023]
Abstract
Objective: Cardiac T2* magnetic resonance imaging (MRI) has recently attracted considerable attention as a non-invasive method for detecting iron overload in various organs in thalassemia major patients. This study aimed to identify the prevalence of cardiac siderosis in thalassemia major patients and evaluate cardiac T2* MRI for monitoring cardiac siderosis before and after patients receive iron chelation therapy and its relation to serum ferritin, left ventricular ejection fraction, and liver iron concentration. The information gathered would be used for the direct monitoring, detection, and treatment of complications early on. Methods: A total of 119 thalassemia major patients were recruited in the present study. The cardiac T2* MRI was compared to serum ferritin levels, liver iron concentration (LIC), and left ventricular ejection fraction. All patients were classified into four groups based on their cardiac siderosis as having normal, marginal, mild to moderate, or severe cardiac iron overload. At the follow-up at years one, three, and five, the cardiac T2* MRI, LIC, serum ferritin, and left ventricular ejection fraction (LVEF) were determined. Results: The prevalence of cardiac siderosis with cardiac T2* MRI ≤ 25 ms was 17.6% (n = 21). There was no correlation between cardiac T2* MRI and serum ferritin, liver iron concentration, and LVEF (p = 0.39, 0.54, and 0.09, respectively). During one year to five years’ follow-up periods, cardiac T2* MRI (ms) in patients with severe cardiac siderosis had significantly improved from 8.5 ± 1.49 at baseline to 33.9 ± 1.9 at five years (p < 0.0001). Patients with severe, mild-moderate, marginal, and no cardiac siderosis had median LIC (mg/g dw) of 23.9 ± 6.5, 21.6 ± 13.3, 25.3 ± 7.7, and 19.9 ± 5.5 at baseline, respectively. Conclusions: This study supports the use of cardiac T2* MRI to monitor cardiac iron overload in patients who have had multiple blood transfusions. Early diagnosis and treatment of patients at risk of cardiac siderosis is a reasonable method of reducing the substantial cardiac mortality burden associated with myocardial siderosis. Cardiac T2* MRI is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy.
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Affiliation(s)
- Narumol Chaosuwannakit
- Radiology Department, Faculty of Medicine, Khon Kaen University, Khon Kaen 40000, Thailand
- Correspondence:
| | - Pattarapong Makarawate
- Internal Medicine Department, Faculty of Medicine, Khon Kaen University, Khon Kaen 40000, Thailand; (P.M.); (C.W.)
| | - Chinnadol Wanitpongpun
- Internal Medicine Department, Faculty of Medicine, Khon Kaen University, Khon Kaen 40000, Thailand; (P.M.); (C.W.)
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Kamperidis V, Vlachou M, Pappa Z, Pantelidou D, Karamitsos T, Papadopoulou D, Kartas A, Boutou A, Ventoulis I, Vlachaki E, Giannakoulas G, Karvounis H. Prediction of long-term survival in patients with transfusion-dependent hemoglobinopathies: Insights from cardiac imaging and ferritin. Hellenic J Cardiol 2021; 62:429-438. [PMID: 33524617 DOI: 10.1016/j.hjc.2021.01.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 12/24/2020] [Accepted: 01/14/2021] [Indexed: 11/19/2022] Open
Abstract
AIMS The current study evaluated the association of echocardiography, cardiac magnetic resonance (CMR), and ferritin data with 10-year survival in thalassemia patients. METHODS Demographics, ferritin, echocardiography, and CMR parameters of stable consecutive thalassemia patients were prospectively collected. RESULTS In total, 75 patients (mean age 37 ± 11 years, 45% male) with thalassemia were included and dichotomized based on their survival status after a median follow-up period of 10.3 [9.6-10.9] years. Older age (HR: 1.071, p = 0.001), ferritin ≥2000 ng/ml (HR: 4.682, p = 0.007) and ≥1700 ng/ml (HR: 7.817, p = 0.002), elevated LV end-diastolic pressure (HR: 1.019, p = 0.044), TR Vmax >2.8 m/s (HR: 6.845, p = 0.005), and CMR T2∗ ≤20 msec (HR: 3.602, p = 0.043) and ≤34 msec (HR: 5.854, p = 0.026) were associated with increased all-cause mortality (primary endpoint). A baseline model including age was created and became more predictive of worse survival by adding TR Vmax >2.8 m/s instead of elevated LV end-diastolic pressure (C index 0.767 vs. 0.760, respectively), ferritin ≥1700 ng/ml instead of ≥2000 ng/ml (C index 0.890 vs. 0.807, respectively), or CMR T2∗≤34 msec instead of ≤20 msec (C index 0.845 vs. 0.839, respectively). Parameters associated with the combined endpoint of cardiac mortality/cardiac hospitalization (secondary endpoint) after adjusting for age were ferritin ≥1700 ng/ml (HR 3.770, p = 0.014), ratio E/A wave >2 (HR 3.565, p = 0.04), TR Vmax >2.8 m/s (HR 4.541, p = 0.049), CMR T2∗ ≤20 ms (HR 9.462, p = 0.001), and CMR T2∗ ≤34 ms (HR 11.735, p = 0.002). The model including age and T2∗ ≤34 ms instead of T2∗ ≤20 ms was more predictive of the secondary endpoint (C-index 0.844 vs 0.838, respectively). CONCLUSIONS In thalassemia patients, TR Vmax >2.8 m/s, ferritin ≥2000 ng/ml, and CMR T2∗ ≤20 ms were associated with worse long-term survival. In the current era of advanced chelation therapy, aiming for ferritin ≤1700 ng/ml and CMR T2∗ ≥34 ms may improve their prognosis.
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Affiliation(s)
- Vasileios Kamperidis
- 1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.
| | - Maria Vlachou
- 1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Zoi Pappa
- 1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | | | - Theodoros Karamitsos
- 1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | | | - Anastasios Kartas
- 1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Afroditi Boutou
- Pulmonary Department, Papanikolaou Hospital, Thessaloniki, Greece
| | - Ioannis Ventoulis
- 1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Efthymia Vlachaki
- Thalassaemia Unit, Ippokratio University Hospital, Thessaloniki, Greece
| | - George Giannakoulas
- 1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Haralambos Karvounis
- 1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
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Hussain S, Hoodbhoy Z, Ali F, Hasan E, Alvi N, Hussain A, Ishrat K, Ur Rahman Z, Qamruddin A, Parvin A, Hasan BS. Reduction of cardiac iron overload by optimising iron chelation therapy in transfusion dependent thalassaemia using cardiac T2* MRI: a quality improvement project from Pakistan. Arch Dis Child 2020; 105:1041-1048. [PMID: 32994214 DOI: 10.1136/archdischild-2020-319203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVES Cardiac T2* MRI (T2*CMR), for accurate estimation of myocardial siderosis, was introduced as part of a QI collaborative to optimise chelation therapy in order to improve cardiac morbidity in transfusion dependent thalassaemia (TDT) patients. We report the impact of this QI initiative from two thalassaemia centres from this collaborative. DESIGN AND SETTING A key driver based quality initiative was implemented to improve chelation in TDT patients registered at these two centres in Karachi, Pakistan. Protocol optimisation and compliance to treatment through training, communication and feedback were used as the drivers for QI intervention. Preintervention variables (demographics, chelation history, T2*CMR, echocardiography and holters) were collected from January 2015 to December 2016) and compared with variables in the post implementation phase (January to December 2019). A standardised adverse event severity for chelators and its management was devised for safe drug therapy as well as ensuring compliance to the regimen. Preintervention and postintervention variables were compared using non-parametric test. P value<0.05 was statistically significant. RESULTS 100 patients with TDT, median age 17 (9-34) years, were included. An increase or stabilisation of T2*CMR was documented in 82% patients in the postintervention phase especially in patients with severe myocardial iron overload (5.5 vs 5.3 ms, p <0.01). Significantly fewer patients had abnormal echocardiographic findings (3.5% vs 26%, p <0.05) in the postintervention versus preintervention period. CONCLUSION This QI initiative improved the chelation therapy leading to improved cardiac status in TDT patients at the participating centres.
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Affiliation(s)
| | - Zahra Hoodbhoy
- Department of Pediatrics and Child Health, The Aga Khan University and Hospital, Karachi, Sindh, Pakistan
| | - Fatima Ali
- Department of Pediatrics and Child Health, The Aga Khan University and Hospital, Karachi, Sindh, Pakistan
| | - Erum Hasan
- Kashif Iqbal Thalassaemia Care Centre, Karachi, Sindh, Pakistan
| | - Najveen Alvi
- Department of Pediatrics and Child Health, The Aga Khan University and Hospital, Karachi, Sindh, Pakistan
| | | | | | | | | | - Azra Parvin
- Fatimid Foundation, Karachi, Sindh, Pakistan
| | - Babar S Hasan
- Department of Pediatrics and Child Health, The Aga Khan University and Hospital, Karachi, Sindh, Pakistan
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Tilt-table Echocardiography Unmasks Early Diastolic Dysfunction in Patients With Hemoglobinopathies. J Pediatr Hematol Oncol 2020; 42:391-397. [PMID: 32287102 DOI: 10.1097/mph.0000000000001799] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Individuals with hemoglobinopathy (sickle cell anemia and thalassemia major) are at risk for cardiac complications such as heart failure and cardiomyopathy. Diastolic dysfunction is known to precede systolic dysfunction in many cardiac diseases. This study sought to determine whether changes in left atrial (LA) function during manipulation of cardiac preload by tilt-table echocardiography can unmask subclinical diastolic dysfunction in pediatric patients with hemoglobinopathies. Eleven sickle cell anemia, 9 transfusion-dependent thalassemia major, and 10 control subjects underwent tilt-table echocardiogram in the supine (loading) and 30-degree upright (unloading) positions and cardiac magnetic resonance imaging (MRI). Echocardiography assessed LA and left ventricular (LV) strain, strain rate, mitral inflow, and annular velocities. MRI assessed LV function, myocardial T1 and T2* for iron deposition. Both thalassemia major and sickle cell anemia patients had normal LV function and no evidence of cardiac iron deposition on MRI T2* measurements. During cardiac loading, controls appropriately increased LA conduit (P=0.002) and reservoir strain (P=0.002), mitral e' velocity (P<0.0001) and medial e' velocity (P=0.002), while the hemoglobinopathy patients showed no change in these parameters. In pediatric sickle cell anemia and thalassemia, tilt-table echocardiography unmasked a failure to augment LA function in response to loading, suggesting altered myocardial relaxation is present, before evidence of iron overload or systolic dysfunction.
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Combined chelation with high-dose deferiprone and deferoxamine to improve survival and restore cardiac function effectively in patients with transfusion-dependent thalassemia presenting severe cardiac complications. Ann Hematol 2020; 99:2289-2294. [DOI: 10.1007/s00277-020-04196-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 07/20/2020] [Indexed: 01/19/2023]
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Vlachou M, Kamperidis V, Giannakoulas G, Karamitsos T, Vlachaki E, Karvounis H. Biochemical and imaging markers in patients with thalassaemia. Hellenic J Cardiol 2020; 62:4-12. [PMID: 32387594 DOI: 10.1016/j.hjc.2020.04.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 04/06/2020] [Accepted: 04/15/2020] [Indexed: 11/15/2022] Open
Abstract
Beta-thalassaemia is a genetic disease with different clinical aspects, which can lead to heart failure with a multifactorial mechanism. Over the last years, growing interest has been reported for biomarkers that may help in the diagnosis, staging and prognosis of heart disease at an early stage, in patients with beta-thalassaemia. This review will highlight the current clinical value of cardiac biomarkers in patients with beta-thalassaemia and the ongoing research for a possible expanded future use.
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Affiliation(s)
- Maria Vlachou
- 1(st) Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Vasileios Kamperidis
- 1(st) Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.
| | - George Giannakoulas
- 1(st) Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Theodoros Karamitsos
- 1(st) Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Efthymia Vlachaki
- Thalassaemia Unit, Ippokratio University Hospital, Thessaloniki, Greece
| | - Haralambos Karvounis
- 1(st) Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
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Li J, Wang P, Li X, Wang Q, Zhang J, Lin Y. Cost-Utility Analysis of four Chelation Regimens for β-thalassemia Major: a Chinese Perspective. Mediterr J Hematol Infect Dis 2020; 12:e2020029. [PMID: 32395218 PMCID: PMC7202351 DOI: 10.4084/mjhid.2020.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 04/14/2020] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE The Iron chelation is essential to prevent iron overload damage of vital organs, like heart, liver, and endocrine glands, in patients with transfusion-dependent thalassemia. The most common chelation regimens for β-thalassemia major (β-TM) patients used in China are a combination therapy of deferoxamine and deferiprone (DFO+DFP), deferoxamine (DFO) monotherapy, deferiprone (DFP) monotherapy and deferasirox (DFX) monotherapy. Such patients use iron chelators their whole lives, resulting in enormous treatment costs. This study analyses the cost-utility of these four regimens from the Chinese healthcare system perspective. METHODS A Markov decision model was used over a 5-year time horizon and was populated using clinical data from a systematic literature review. We obtained utility data from local and previous research. Costs were estimated using Chinese national sources. RESULTS From the base-case analysis results, DFP was the most cost-effective chelation regimen, followed by DFO, DFX, and DFO+DFP. DFP had 97.32%, 99.43%, and 58.04% likelihood of being cost-effective versus DFX, DFO+DFP, and DFO, respectively, at a payment threshold of 193,932.00 CNY/QALY (QALY, quality-adjusted life-year). CONCLUSIONS DFP was the most cost-effective chelation regimen for β-TM patients, followed by DFO, DFX, and DFO+DFP. Using DFP as the primary treatment regimen may potentially result in cost-savings and QALY gains for the Chinese healthcare system. To increase these benefits, the Chinese government should take measures to lower DFX and DFO drug costs, and Chinese clinicians should choose the cheaper DFX and DFO, increase the utility of DFO+DFP and reduce mortality and morbidity of DFP. Changes in influential parameters easily affect the results of DFX versus DFO+DFP and of DFP versus DFO; clinicians should focus on such parameters and adjust the regimens accordingly.
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Affiliation(s)
- Jialian Li
- Department of Pharmacy, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
| | - Peng Wang
- Department of Pharmacy, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
| | - Xue Li
- Department of Pharmacy, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
| | - Qiaoyu Wang
- Department of Pharmacy, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
| | - Jiayou Zhang
- Department of Hematology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
| | - Yong Lin
- Department of Pharmacy, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, China
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The History of Deferiprone (L1) and the Paradigm of the Complete Treatment of Iron Overload in Thalassaemia. Mediterr J Hematol Infect Dis 2020; 12:e2020011. [PMID: 31934321 PMCID: PMC6951358 DOI: 10.4084/mjhid.2020.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 12/18/2019] [Indexed: 01/19/2023] Open
Abstract
Deferiprone (L1) was originally designed, synthesised and screened in vitro and in vivo in 1981 by Kontoghiorghes G. J. following his discovery of the novel alpha-ketohydroxypyridine class of iron chelators (1978–1981), which were intended for clinical use. The journey through the years for the treatment of thalassaemia with L1 has been a very difficult one with an intriguing turn of events, which continue until today. Despite many complications, such as the extensive use of L1 suboptimal dose protocols, the aim of chelation therapy-namely, the complete removal of excess iron in thalassaemia major patients, has been achieved in most cases following the introduction of specific L1 and L1/deferoxamine combinations. Many such patients continue to maintain normal iron stores. Thalassemia has changed from a fatal to chronic disease; also thanks to L1 therapy and thalassaemia patients are active professional members in all sectors of society, have their own families with children and grandchildren and their lifespan is approaching that of normal individuals. No changes in the low toxicity profile of L1 have been observed in more than 30 years of clinical use and prophylaxis against the low incidence of agranulocytosis is maintained using mandatory monitoring of weekly white blood cells’ count. Thousands of thalassaemia patients are still denied the cardioprotective and other beneficial effects of L1 therapy. The safety of L1 in thalassaemia and other non-iron loaded diseases resulted in its selection as one of the leading therapeutics for the treatment of Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration and other similar cases. There are also increasing prospects for the application of L1 as a main, alternative or adjuvant therapy in many pathological conditions including cancer, infectious diseases and as a general antioxidant for diseases related to free radical pathology.
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Paul A, Thomson VS, Refaat M, Al-Rawahi B, Taher A, Nadar SK. Cardiac involvement in beta-thalassaemia: current treatment strategies. Postgrad Med 2019; 131:261-267. [DOI: 10.1080/00325481.2019.1608071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Amal Paul
- Department of Cardiology, Christian Medical college and Hospital, Vellore, India
| | - Viji S Thomson
- Department of Cardiology, Christian Medical college and Hospital, Vellore, India
| | - Marwan Refaat
- Departments of: Internal Medicine, Biochemistry & Molecular Genetics, American University of Beirut Medical Center, Beirut, Lebanon
| | - Bader Al-Rawahi
- Department of Hematology, Sultan Qaboos University Hospital, Muscat Oman
| | - Ali Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sunil K Nadar
- Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
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Derchi G, Dessì C, Bina P, Cappellini MD, Piga A, Perrotta S, Tartaglione I, Giuditta M, Longo F, Origa R, Quarta A, Pinto V, Forni GL. Risk factors for heart disease in transfusion-dependent thalassemia: serum ferritin revisited. Intern Emerg Med 2019; 14:365-370. [PMID: 29948832 DOI: 10.1007/s11739-018-1890-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Accepted: 06/06/2018] [Indexed: 01/19/2023]
Abstract
Heart disease remains a leading cause of morbidity and mortality in transfusion-dependent thalassemia (TDT), which can be attributed to several factors but primarily develops in the setting of iron overload. This was a retrospective cohort study utilizing Webthal® patient data from five major centers across Italy. Patients without heart disease were followed-up for 10 years (2000-2010) and data were collected for demographics, splenectomy status, serum ferritin and hemoglobin levels, and comorbidities associated with heart disease. Among 379 patients analyzed (mean age 22.9 ± 5.1 years, 47.8% men), 44 (cumulative incidence: 11.6%) developed heart disease during the period of observation. Splenectomy (p = 0.002) and serum ferritin level (p < 0.001) were the only risk factors with significant association with heart disease. A serum ferritin threshold of ≥ 3000 ng/mL was the best predictor for the development of heart disease (86.4% sensitivity and 92.8% specificity, AUC: 0.912, 95% CI 0.852-0.971, p < 0.001). On multivariate analysis, only a serum ferritin level ≥ 3000 ng/mL remained significantly and independently associated with increased risk of heart disease (HR: 44.85, 95% CI 18.85-106.74), with a 5- and 10-year heart disease-free survival of 58 and 39%. The association between iron overload and heart disease in patients with TDT is confirmed, yet a new serum ferritin level of 3000 ng/mL to flag increased risk is suggested.
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Affiliation(s)
| | - Carlo Dessì
- Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy
| | - Patrizio Bina
- Ospedale Regionale per le Microcitemie, ASL8, Cagliari, Italy
| | - Maria Domenica Cappellini
- Department of Clinical Sciences and Community, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Antonio Piga
- Department of Clinical and Biological Sciences, Università di Torino, Turin, Italy
| | - Silverio Perrotta
- Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy
| | - Immacolata Tartaglione
- Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy
| | - Marianna Giuditta
- Department of Clinical Sciences and Community, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Filomena Longo
- Department of Clinical and Biological Sciences, Università di Torino, Turin, Italy
| | - Raffaella Origa
- Thalassemia Unit, Department of Public Health, Clinical and Molecular Medicine, Università di Cagliari, Cagliari, Italy
| | | | - Valeria Pinto
- Ematologia-Centro della Microcitemia e Anemie Congenite, Ospedale Galliera, Via Volta 6, 16128, Genoa, Italy
| | - Gian Luca Forni
- Ematologia-Centro della Microcitemia e Anemie Congenite, Ospedale Galliera, Via Volta 6, 16128, Genoa, Italy.
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32
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Lin CH, Chen X, Wu CC, Wu KH, Song TS, Weng TF, Hsieh YW, Peng CT. Therapeutic mechanism of combined oral chelation therapy to maximize efficacy of iron removal in transfusion-dependent thalassemia major - a pilot study. Expert Rev Hematol 2019; 12:265-272. [PMID: 30920854 DOI: 10.1080/17474086.2019.1593823] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Three iron chelators are used to treat transfusion-dependent beta-thalassemia: desferrioxamine (DFO), deferasirox (DFX), and deferiprone (DFP). Compliance is low for DFO as it cannot be administered orally. Combined administration of DFP and DFX is orally available, however, the therapeutic mechanism is unknown. This pilot study investigated the iron removal mechanisms of DFX and DFP treatment in patients with transfusion-dependent thalassemia major. METHODS Each patient received three treatments sequentially: (1) DFX monotherapy, (2) DFP monotherapy, and (3) DFX/DFP combination therapy with a four-day washout period between each treatment. Urine and stool specimens were collected to determine the primary outcome of iron excretion volumes. RESULTS The mean iron excretion was seven times higher after combination therapy with DFX and DFP. Monotherapies also increased excretions volumes, though to a significantly lesser degree. Combined administration of DFX and DFP achieves maximum iron removal in transfusion-dependent thalassemia major compared to monotherapy with either drug. CONCLUSIONS We suggest combination therapy in chronic severe iron overload cases, especially for patients in poor compliance with DFO/DFP combination therapy or those exhibiting poor iron removal from DFX or DFP monotherapy.
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Affiliation(s)
- Chien-Heng Lin
- a Division of Pediatric Pulmonology , China Medical University Children's Hospital , Taichung , Taiwan.,b Department of Biomedical Imaging and Radiological Science , College of Health Care, China Medical University , Taichung , Taiwan
| | - Xianxiu Chen
- c Department of Public Health , China Medical University , Taichung , Taiwan
| | - Chin-Ching Wu
- c Department of Public Health , China Medical University , Taichung , Taiwan
| | - Kang-Hsi Wu
- d Division of Pediatric Hematology and Oncology , China Medical University Children's Hospital , Taichung , Taiwan
| | - Ta-Shu Song
- e School of Pharmacy , China Medical University , Taichung , Taiwan.,f Research Department , Yung Shin Pharmaceutical Industrial Co .., Taichung , Taiwan
| | - Te-Fu Weng
- d Division of Pediatric Hematology and Oncology , China Medical University Children's Hospital , Taichung , Taiwan
| | - Yow-Wen Hsieh
- g Department of Pharmacy , China Medical University Hospital , Taichung , Taiwan
| | - Ching-Tien Peng
- d Division of Pediatric Hematology and Oncology , China Medical University Children's Hospital , Taichung , Taiwan.,h Department of Biotechnology , Asia University , Taichung , Taiwan
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Casale M, Filosa A, Ragozzino A, Amendola G, Roberti D, Tartaglione I, De Michele E, Cozzolino D, Rispoli G, Palmieri F, Pugliese U, Scianguetta S, Signoriello G, Musallam KM, Perrotta S. Long-term improvement in cardiac magnetic resonance in β-thalassemia major patients treated with deferasirox extends to patients with abnormal baseline cardiac function. Am J Hematol 2019; 94:312-318. [PMID: 30489651 DOI: 10.1002/ajh.25370] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/22/2018] [Accepted: 11/26/2018] [Indexed: 01/21/2023]
Abstract
The management of iron overload in thalassemia has changed dramatically since the implementation of magnetic resonance imaging, which allows detection of preclinical iron overload and prevention of clinical complications. This study evaluated the effect of deferasirox (DFX), the newest once-daily oral chelator, on cardiac function, iron overload and cardiovascular events over a longer follow up in a "real world" setting. Longitudinal changes in cardiac magnetic resonance T2*, cardiac function parameters and cardiovascular clinical events were assessed in a cohort of 98 TM patients exposed to DFX for a mean of 6.9 years (range 1.8-11.6 years). No cardiac death or incident heart failure occurred. Cardiac T2* significantly increased (+2.6 ± 11.9 msec; P = 0.035) in the whole population, with a significantly greater increase (+11.6 ± 15.5 msec, P = 0.019) in patients with cardiac iron overload (T2* <20 ms). A significant improvement in left-ventricular ejection fraction (LVEF) (from 50.6 ± 6 to 60.2 ± 5; P = 0.001) was observed in 11 (84.6%) out of 13 patients who normalized cardiac function (LVEF >56%). Arrhythmias were the most frequent cardiac adverse event noted but none led to DFX discontinuation. Our data indicate that DFX is effective in maintaining cardiac iron level in the normal range and in improving cardiac iron overload. No heart failure or cardiac death was reported over this longer observation up to 12 years. For the first time, a DFX-induced improvement in LVEF was observed in a subgroup of patients with abnormal cardiac function at baseline, a preliminary observation which deserves further evaluation.
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Affiliation(s)
- Maddalena Casale
- Department of Woman, Child and General and Specialized SurgeryUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
| | - Aldo Filosa
- Rare Blood Cell UnitAORN Cardarelli Naples Italy
| | - Alfonso Ragozzino
- Department of RadiologyOspedale S. Maria delle Grazie Pozzuoli Italy
| | | | - Domenico Roberti
- Department of Woman, Child and General and Specialized SurgeryUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
| | - Immacolata Tartaglione
- Department of Woman, Child and General and Specialized SurgeryUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
| | - Elisa De Michele
- Immunotransfusion Medicine UnitAOU OO.RR. S. Giovanni di Dio e Ruggi d'Aragona Salerno Italy
| | - Domenico Cozzolino
- Department of Internal MedicineUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
| | - Giuliana Rispoli
- Department of Woman, Child and General and Specialized SurgeryUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
| | | | - Umberto Pugliese
- Department of Woman, Child and General and Specialized SurgeryUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
| | - Saverio Scianguetta
- Department of Woman, Child and General and Specialized SurgeryUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
| | - Giuseppe Signoriello
- Department of Mental Health and Preventive MedicineUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
| | | | - Silverio Perrotta
- Department of Woman, Child and General and Specialized SurgeryUniversità degli Studi della Campania Luigi Vanvitelli Naples Italy
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Jhinger P, Sobti PC, Kaushal S, Kakkar S. Combination of two oral iron chelators in patients with thalassemia major. PEDIATRIC HEMATOLOGY ONCOLOGY JOURNAL 2018. [DOI: 10.1016/j.phoj.2018.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Abstract
Iron-overload syndromes may be hereditary or acquired. Patients may be asymptomatic early in the disease. Once heart failure develops, there is rapid deterioration. Cardiac hemochromatosis is characterized by a dilated cardiomyopathy with dilated ventricles, reduced ejection fraction, and reduced fractional shortening. Deposition of iron may occur in the entire cardiac conduction system, especially the atrioventricular node. Cardiac hemochromatosis should be considered in any patient with unexplained heart failure. Screening for systemic iron overload with serum ferritin and transferin saturation should be performed. If these tests are consistent with iron overload, further noninvasive and histologic confirmation is indicated to confirm organ involvement with iron overload. Cardiac magnetic resonance imaging is superior to other diagnostic tests since it can quantitatively assess myocardial iron load. Therapeutic phlebotomy is the therapy of choice in nonanemic patients with cardiac hemochromatosis. Therapeutic phlebotomy should be started in men with serum ferritin levels of 300 μg/l or more and in women with serum ferritin levels of 200 μg/l or more. Therapeutic phlebotomy consists of removing 1 unit of blood (450 to 500 ml) weekly until the serum ferritin level is 10 to 20 μg/l and maintenance of the serum ferritin level at 50 μg/l or lower thereafter by periodic removal of blood. Phlebotomy is not a treatment option in patients with anemia (secondary iron-overload disorders) nor in patients with severe congestive heart failure. In these patients, the treatment of choice is iron chelation therapy.
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Affiliation(s)
- Wilbert S Aronow
- Cardiology Division, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY, USA
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Abstract
PURPOSE OF REVIEW Thalassemia is the most common form of inherited anemia, characterized by variable clinical phenotypes. The purpose of this review is to summarize the transfusion support in thalassemia patients and the management of transfusion-related iron overload. RECENT FINDINGS The most recent evidence on transfusion strategy and iron chelation therapy in thalassemia arising from clinical trials as well as from recommendation guidelines are critically discussed. SUMMARY Enhancements in the global care of thalassemia, resulting from the combination of an appropriate transfusion approach and iron chelation therapy, have produced a significant improvement in the quality of life and, finally, in the prognosis of patients affected by this inherited hematologic disorder.
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Increased sympathovagal imbalance evaluated by heart rate variability is associated with decreased T2* MRI and left ventricular function in transfusion-dependent thalassemia patients. Biosci Rep 2018; 38:BSR20171266. [PMID: 29330222 PMCID: PMC5794499 DOI: 10.1042/bsr20171266] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 12/19/2017] [Accepted: 01/08/2018] [Indexed: 12/24/2022] Open
Abstract
Early detection of iron overload cardiomyopathy is an important strategy for decreasing the mortality rate of patients with transfusion-dependent thalassemia (TDT). Although cardiac magnetic resonance (CMR) T2* is effective in detecting cardiac iron deposition, it is costly and not generally available. We investigated whether heart rate variability (HRV) can be used as a screening method of iron overload cardiomyopathy in TDT patients. HRV, evaluated by 24-h Holter monitoring, non-transferrin bound iron (NTBI), serum ferritin, left ventricular (LV) ejection fraction (LVEF), and CMR-T2* were determined. Patients with a cardiac iron overload condition had a significantly higher low frequency/high frequency (LF/HF) ratio than patients without a cardiac iron overload condition. Log-serum ferritin (r = -0.41, P=0.008), serum NTBI (r = -0.313, P=0.029), and LF/HF ratio (r = -0.286, P=0.043) showed a significant correlation with CMR-T2*, however only the LF/HF ratio was significantly correlated with LVEF (r = -0.264, P=0.043). These significant correlations between HRV and CMR-T2* and LVEF in TDT confirmed the beneficial role of HRV as a potential early screening tool of cardiac iron overload in thalassemia patients, especially in a medical center in which CMR T2* is not available. A larger number of TDT patients with cardiac iron overload are needed to confirm this finding.
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Mavrogeni S, Kolovou G, Bigalke B, Rigopoulos A, Noutsias M, Adamopoulos S. Transplantation in patients with iron overload: is there a place for magnetic resonance imaging? : Transplantation in iron overload. Heart Fail Rev 2018; 23:173-180. [PMID: 29359261 DOI: 10.1007/s10741-018-9670-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In iron overload diseases (thalassemia, sickle cell, and myelodysplastic syndrome), iron is deposited in all internal organs, leading to functional abnormalities. Hematopoietic stem cell transplantation (HSCT) is the only treatment offering a potential cure in these diseases. Our aim was to describe the experience in the field and the role of magnetic resonance imaging in the evaluation of iron overload before and after HSCT. Magnetic resonance imaging (MRI), using T2*, is the most commonly used tool to diagnose myocardial-liver iron overload and guide tailored treatment. Currently, HSCT offers complete cure in thalassemia major, after overcoming the immunologic barrier, and should be considered for all patients who have a suitable donor. The overall thalassemia-free survival of low-risk, HLA-matched sibling stem cell transplantation patients is 85-90%, with a 95% overall survival. The problems of rejection and engraftment are improving with the use of adequate immunosuppression. However, a detailed iron assessment of both heart and liver is necessary for pre- and post-transplant evaluation. In iron overload diseases, heart and liver iron evaluation is indispensable not only for the patients' survival, but also for evaluation before and after HSCT.
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Affiliation(s)
- Sophie Mavrogeni
- Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61, Palaeo Faliro, Athens, Greece. .,, Athens, Greece.
| | - Genovefa Kolovou
- Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61, Palaeo Faliro, Athens, Greece
| | - Boris Bigalke
- Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin (CBF), Hindenburgdamm 30, 12200, Berlin, Germany
| | - Angelos Rigopoulos
- Department of Cardiology, Leopoldina Hospital, 97422, Schweinfurt, Germany
| | - Michel Noutsias
- Department of Internal Medicine I, Division of Cardiology, Pneumology, Angiology and Intensive Medical Care, University Hospital Jena, Friedrich-Schiller-University Jena, Am Klinikum 1, 07747, Jena, Germany
| | - Stamatis Adamopoulos
- Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61, Palaeo Faliro, Athens, Greece
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Abstract
Introduction of MRI techniques for identifying and monitoring tissue iron overload and the current understanding of iron homeostasis in transfusion-dependent (TDT) and non-transfusion-dependent thalassemia have allowed for a more robust administration of iron chelation therapies. The development of safe and efficient oral iron chelators and the insights gained from large-scale prospective studies using these agents have improved iron overload management. A significant reduction in iron toxicity-induced morbidity and mortality and improvements in quality of life were observed in TDT. The appropriate management of tissue-specific iron loading in TDT has been portrayed using evidence-based data obtained from investigational studies.
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Affiliation(s)
- Yesim Aydinok
- Department of Pediatric Hematology and Oncology, Ege University Children's Hospital, Bornova, Izmir 35100, Turkey.
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Abstract
Inherited haemoglobin disorders, including thalassaemia and sickle-cell disease, are the most common monogenic diseases worldwide. Several clinical forms of α-thalassaemia and β-thalassaemia, including the co-inheritance of β-thalassaemia with haemoglobin E resulting in haemoglobin E/β-thalassaemia, have been described. The disease hallmarks include imbalance in the α/β-globin chain ratio, ineffective erythropoiesis, chronic haemolytic anaemia, compensatory haemopoietic expansion, hypercoagulability, and increased intestinal iron absorption. The complications of iron overload, arising from transfusions that represent the basis of disease management in most patients with severe thalassaemia, might further complicate the clinical phenotype. These pathophysiological mechanisms lead to an array of clinical manifestations involving numerous organ systems. Conventional management primarily relies on transfusion and iron-chelation therapy, as well as splenectomy in specific cases. An increased understanding of the molecular and pathogenic factors that govern the disease process have suggested routes for the development of new therapeutic approaches that address the underlying chain imbalance, ineffective erythropoiesis, and iron dysregulation, with several agents being evaluated in preclinical models and clinical trials.
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Affiliation(s)
- Ali T Taher
- Department of Internal Medicine, American University of Beirut Medical Centre, Beirut, Lebanon.
| | - David J Weatherall
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Maria Domenica Cappellini
- Department of Clinical Sciences and Community, University of Milan, IRCCS Ca'Granda Foundation Maggiore Policlinico Hospital, Milan, Italy
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Taher AT, Saliba AN. Iron overload in thalassemia: different organs at different rates. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2017; 2017:265-271. [PMID: 29222265 PMCID: PMC6142532 DOI: 10.1182/asheducation-2017.1.265] [Citation(s) in RCA: 178] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic determinants. Iron overload is associated with increased morbidity in both patients with transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The predominant mechanisms driving the process of iron loading include increased iron burden secondary to transfusion therapy in TDT and enhanced intestinal absorption secondary to ineffective erythropoiesis and hepcidin suppression in NTDT. Different organs are affected differently by iron overload in TDT and NTDT owing to the underlying iron loading mechanism and rate of iron accumulation. Serum ferritin measurement and noninvasive imaging techniques are available to diagnose iron overload, quantify its extent in different organs, and monitor clinical response to therapy. This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox. Other novel experimental options for treatment and prevention of complications associated with iron overload in thalassemia are briefly discussed.
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Affiliation(s)
- Ali T. Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; and
| | - Antoine N. Saliba
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
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Restrictive Cardiomyopathies: The Importance of Noninvasive Cardiac Imaging Modalities in Diagnosis and Treatment-A Systematic Review. Radiol Res Pract 2017; 2017:2874902. [PMID: 29270320 PMCID: PMC5705874 DOI: 10.1155/2017/2874902] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 11/02/2017] [Indexed: 12/19/2022] Open
Abstract
Restrictive cardiomyopathy (RCM) is the least common among cardiomyopathies. It can be idiopathic, familial, or secondary to systematic disorders. Marked increase in left and/or right ventricular filling pressures causes symptoms and signs of congestive heart failure. Electrocardiographic findings are nonspecific and include atrioventricular conduction and QRS complex abnormalities and supraventricular and ventricular arrhythmias. Echocardiography and cardiac magnetic resonance (CMR) play a major role in diagnosis. Echocardiography reveals normal or hypertrophied ventricles, preserved systolic function, marked biatrial enlargement, and impaired diastolic function, often with restrictive filling pattern. CMR offering a higher spatial resolution than echocardiography can provide detailed information about anatomic structures, perfusion, ventricular function, and tissue characterization. CMR with late gadolinium enhancement (LGE) and novel approaches (myocardial mapping) can direct the diagnosis to specific subtypes of RCM, depending on the pattern of scar formation. When noninvasive studies have failed, endomyocardial biopsy is required. Differentiation between RCM and constrictive pericarditis (CP), nowadays by echocardiography, is important since both present as heart failure with normal-sized ventricles and preserved ejection fraction but CP can be treated by means of anti-inflammatory and surgical treatment, while the treatment options of RCM are dictated by the underlying condition. Prognosis is generally poor despite optimal medical treatment.
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A Comparison Between MRIT2 and NT-ProBNP in Early Detection of Heart Diseases in Thalassemia Major Patients: A Cross-Sectional Study. Indian J Hematol Blood Transfus 2017; 33:541-544. [PMID: 29075066 DOI: 10.1007/s12288-017-0797-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/21/2017] [Indexed: 10/20/2022] Open
Abstract
One of the most common causes of mortality in major thalassemia is cardiac complications. Despite existence of several methods for diagnosis of cardiac complications in thalassemia, this sequel persists as a major problem in these patients. The aim of this study is to compare the level of serum NT-ProBNP and cardiac MRI T2* in early detection and treatment of cardiac disorders in beta thalassemia major patients. 35 major thalassemic patients on regular transfusion were selected in our center from 2013 to 2014. All of the patients were at least 8 years old. NT-ProBNP and MRIT2* analyses were carried out for these patients, and consequently the findings were compared together and analyzed. There is a strong correlation between NT-ProBNP and MRIT2* (p value < 0.001) in early detection of cardiac disorders. NT-ProBNP is an important marker for diagnosis of cardiac complications before emergence of heart failure in thalassemic patients. Given the findings of this study, it is recommended that this marker be used on a regular basis for thalassemic patients on regular transfusion.
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Kwiatkowski JL. Current recommendations for chelation for transfusion-dependent thalassemia. Ann N Y Acad Sci 2017; 1368:107-14. [PMID: 27186943 DOI: 10.1111/nyas.13088] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 04/12/2016] [Indexed: 01/19/2023]
Abstract
Regular red cell transfusions used to treat thalassemia cause iron loading that must be treated with chelation therapy. Morbidity and mortality in thalassemia major are closely linked to the adequacy of chelation. Chelation therapy removes accumulated iron and detoxifies iron, which can prevent and reverse much of the iron-mediated organ injury. Currently, three chelators are commercially available--deferoxamine, deferasirox, and deferiprone--and each can be used as monotherapy or in combination. Close monitoring of hepatic and cardiac iron burden is central to tailoring chelation. Other factors, including properties of the individual chelators, ongoing transfusional iron burden, and patient preference, must be considered. Monotherapy generally is utilized if the iron burden is in an acceptable or near-acceptable range and the dose is adjusted accordingly. Combination chelation often is employed for patients with high iron burden, iron-related organ injury, or where adverse effects of chelators preclude administration of an appropriate chelator dose. The combination of deferoxamine and deferiprone is the best studied, but increasing data are available on the safety and efficacy of newer chelator combinations, including deferasirox with deferoxamine and the oral-only combination of deferasirox with deferiprone. The expanding chelation repertoire should enable better control of iron burden and improved outcomes.
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Affiliation(s)
- Janet L Kwiatkowski
- Children's Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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45
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Belmont A, Kwiatkowski JL. Deferiprone for the treatment of transfusional iron overload in thalassemia. Expert Rev Hematol 2017; 10:493-503. [DOI: 10.1080/17474086.2017.1318052] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Ami Belmont
- Alpert Medical School of Brown University, Providence, RI, USA
| | - Janet L. Kwiatkowski
- Children’s Hospital of Philadelphia, Division of Hematology and Perelman School of Medicine at the University of Pennsylvania, Department of Pediatrics, Philadelphia, PA, USA
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Update on the Role of Cardiac Magnetic Resonance in Acquired Nonischemic Cardiomyopathies. J Thorac Imaging 2017; 31:348-366. [PMID: 27438188 DOI: 10.1097/rti.0000000000000226] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cardiomyopathies refer to a variety of myocardial disorders without underlying coronary artery disease, valvular heart disease, hypertension, or congenital heart disease. Several imaging modalities are available, but cardiac magnetic resonance (CMR) has now established itself as a crucial imaging technique in the evaluation of several cardiomyopathies. It not only provides comprehensive information on structure and function, but also can perform tissue characterization, which helps in establishing the etiology of cardiomyopathy. CMR is also useful in establishing the diagnosis, providing guidance for endomyocardial biopsy, accurate quantification of function, volumes, and fibrosis, prognostic determination, risk stratification, and monitoring response to therapy. In this article, we review the current role of CMR in the evaluation of several acquired nonischemic cardiomyopathies, particularly focusing on recent advances in knowledge. We also discuss in detail a select group of common acquired nonischemic cardiomyopathies.
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Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol 2017; 178:676-688. [DOI: 10.1111/bjh.14712] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Rosario Di Maggio
- Campus of Haematology Franco and Piera Cutino; AOR Villa Sofia-V. Cervello; Palermo Italy
| | - Aurelio Maggio
- Campus of Haematology Franco and Piera Cutino; AOR Villa Sofia-V. Cervello; Palermo Italy
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Efficacy and Safety of Combined Oral Chelation With Deferiprone and Deferasirox in Children With β-Thalassemia Major: An Experience From North India. J Pediatr Hematol Oncol 2017; 39:209-213. [PMID: 28221264 DOI: 10.1097/mph.0000000000000780] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE A combination of desferrioxamine with either deferiprone (DFP) or deferasirox (DFX) for patients with β-thalassemia major who do not achieve negative iron balance with monotherapy has been studied widely. However, poor compliance resulting from the need for parentral administration of desferrioxamine and its cost necessicitates combining 2 oral chelators. METHODS A prospective study was conducted in patients with transfusion-dependent β-thalassemia major in a tertiary care center over 2 years. Patients on either DFP or DFX who were not improving on monotherapy over a long period and persistently maintaining serum ferritin >2500 µg/L were enrolled. Efficacy was assessed by serum ferritin levels assessed at 12 months and 2 years. Complete blood counts and liver and kidney function tests were monitored to assess the safety of the combination of drugs. RESULTS In total, 33 patients with a mean age of 12.67 years (7.5 to 17.5 y) and a mean ferritin of 4835.2394±1443.85 µg/L formed the study cohort.In total, 28 patients completed the 1-year study period; and 12 patients completed 2 years. Mean serum ferritin reduction at 1 and 2 years was 34.99%±18.13% (range, -34.36% to 56.17%) and 44.67%±13.78% (range, 22.17% to 62.74%), respectively. The combination therapy was well tolerated. CONCLUSIONS Combined oral chelation with DFP and DFX has better efficacy than either drug used alone. The combination of drugs was well tolerated and no new adverse effects were observed.
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Kirk P, Sheppard M, Carpenter JP, Anderson L, He T, St Pierre T, Galanello R, Catani G, Wood J, Fucharoen S, Porter JB, Walker JM, Forni GL, Pennell DJ. Post-mortem study of the association between cardiac iron and fibrosis in transfusion dependent anaemia. J Cardiovasc Magn Reson 2017; 19:36. [PMID: 28343449 PMCID: PMC5367003 DOI: 10.1186/s12968-017-0349-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 03/01/2017] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Heart failure related to cardiac siderosis remains a major cause of death in transfusion dependent anaemias. Replacement fibrosis has been reported as causative of heart failure in siderotic cardiomyopathy in historical reports, but these findings do not accord with the reversible nature of siderotic heart failure achievable with intensive iron chelation. METHODS Ten whole human hearts (9 beta-thalassemia major, 1 sideroblastic anaemia) were examined for iron loading and fibrosis (replacement and interstitial). Five had died from heart failure, 4 had cardiac transplantation for heart failure, and 1 had no heart failure (death from a stroke). Heart samples iron content was measured using atomic emission spectroscopy. Interstitial fibrosis was quantified by computer using picrosirius red (PSR) staining and expressed as collagen volume fraction (CVF) with normal value for left ventricle <3%. RESULTS The 9 hearts affected by heart failure had severe iron loading with very low T2* of 5.0 ± 2.0 ms (iron concentration 8.5 ± 7.0 mg/g dw) and diffuse granular myocardial iron deposition. In none of the 10 hearts was significant macroscopic replacement fibrosis present. In only 2 hearts was interstitial fibrosis present, but with low CVF: in one patient with no cardiac siderosis (death by stroke, CVF 5.9%) and in a heart failure patient (CVF 2%). In the remaining 8 patients, no interstitial fibrosis was seen despite all having severe cardiac siderosis and heart failure (CVF 1.86% ±0.87%). CONCLUSION Replacement cardiac fibrosis was not seen in the 9 post-mortem hearts from patients with severe cardiac siderosis and heart failure leading to death or transplantation, which contrasts markedly to historical reports. Minor interstitial fibrosis was also unusual and very limited in extent. These findings accord with the potential for reversibility of heart failure seen in iron overload cardiomyopathy. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00520559.
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Affiliation(s)
- Paul Kirk
- Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, Sydney Street, SW3 6NP, London, UK
- National Heart and Lung Institute, Imperial College, London, UK
| | - Mary Sheppard
- National Heart and Lung Institute, Imperial College, London, UK
- CRY Centre for Cardiac Pathology, Royal Brompton Hospital, London, UK
| | - John-Paul Carpenter
- Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, Sydney Street, SW3 6NP, London, UK
- National Heart and Lung Institute, Imperial College, London, UK
| | - Lisa Anderson
- Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, Sydney Street, SW3 6NP, London, UK
- National Heart and Lung Institute, Imperial College, London, UK
| | - Taigang He
- Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, Sydney Street, SW3 6NP, London, UK
- National Heart and Lung Institute, Imperial College, London, UK
| | | | | | | | - John Wood
- Children’s Hospital, Los Angeles, USA
| | | | - John B Porter
- The Hatter Cardiovascular Institute, University College Hospital, London, UK
| | - J Malcolm Walker
- The Hatter Cardiovascular Institute, University College Hospital, London, UK
| | | | - Dudley J Pennell
- Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, Sydney Street, SW3 6NP, London, UK
- National Heart and Lung Institute, Imperial College, London, UK
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Origa R, Anni F, Mereu L, Follesa I, Campus S, Dessì C, Foschini ML, Leoni G, Moi P, Morittu M, Orecchia V, Perra M, Zappu A, Podda RA. Causes of hospital admission in children and adults with transfusion-dependent thalassemia in Sardinia, 2000–2015. Ann Hematol 2017; 96:1041-1042. [DOI: 10.1007/s00277-017-2963-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 02/20/2017] [Indexed: 12/01/2022]
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